CENTER FOR VACCINE INNOVATION AND ACCESS The RTS,S malaria vaccine First malaria vaccine will be piloted in areas of three African countries through routine immunization programs

Summary the vaccine’s role in reducing childhood deaths and severe malaria, and its safety in the context of routine use. Data and Malaria kills more than 400,000 people a year worldwide and information from the MVIP will inform a WHO policy causes illness in tens of millions more, with most deaths recommendation on the broader use of the vaccine. RTS,S has occurring among young children living in sub-Saharan Africa. been approved for use in the pilot evaluation and Phase 4 Although existing interventions have helped to reduce malaria studies by the national regulatory authority in each of the three deaths significantly over the past 15 years, a vaccine could add participating countries. an important complementary tool for malaria control efforts. Financing for the MVIP has been mobilized through an RTS,S/AS01 (RTS,S) is the first malaria vaccine shown to unprecedented collaboration among three global health funding provide partial protection against malaria in young children, and bodies: Gavi, the Vaccine Alliance; the Global Fund to Fight the first to be provided to young children through national AIDS, Tuberculosis and Malaria; and Unitaid. PATH’s activities immunization programs in three sub-Saharan African are also supported by other donors, including the ExxonMobil countries—Ghana, Kenya, and Malawi. These countries are Foundation. However, additional resources will be needed to introducing the vaccine in selected areas as part of a large- bring this vaccine into wide-scale use. scale pilot implementation program coordinated by the World Health Organization (WHO), in collaboration with the ministry of health in each country and with international partners, including PATH and GSK, manufacturer of the vaccine.

The efficacy of the RTS,S vaccine was established in a Phase 3 clinical trial that concluded in 2014. In the trial, children who received four doses of the vaccine had significantly lower risk of developing malaria, including severe malaria. A stringent regulatory authority—the European Medicines Agency (EMA)— issued a positive scientific opinion on the vaccine in July 2015, concluding that the benefits of the vaccine outweigh the risks. As with other new vaccines, and in line with national regulations, the safety profile for RTS,S will continue to be monitored as the vaccine is introduced more widely.

In January 2016, WHO endorsed the joint recommendation of two advisory bodies and recommended pilot implementation of Mother and the child who received the first dose of the malaria vaccine at Mitundu Community Health Center, Malawi. (Photo: PATH). the vaccine in three to five settings in sub-Saharan Africa. In response to that recommendation, a country-led, WHO- Development history of RTS,S coordinated Malaria Vaccine Implementation Programme (MVIP) has been designed to further understand the operational RTS,S was created in 1987 by scientists working at GSK issues in using the vaccine in the context of other malaria laboratories. Early clinical development was conducted in interventions. The MVIP will specifically assess the feasibility of collaboration with the Walter Reed Army Institute for Research. administering the required four doses of the vaccine in children, In January 2001, GSK and PATH’s Malaria Vaccine Initiative,

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Street Address path.org 2201 Westlake Avenue Suite 200 Seattle, WA 98121 USA with grant funds from the Bill & Melinda Gates Foundation to WHO officially adopted the SAGE/MPAC recommendation in PATH, entered into a public-private partnership to develop January 2016, recognizing the considerable public health RTS,S for young children living in malaria-endemic regions in potential of the vaccine, while also acknowledging the need for sub-Saharan Africa. further evaluation before considering its wide-scale deployment.6 RTS,S aims to trigger the immune system when the Plasmodium falciparum malaria parasite enters the human host’s bloodstream through a mosquito bite and infects liver Looking ahead cells. The vaccine is designed to prevent the parasite from The pilot implementation was designed as a six-year program, infecting the liver, where it can mature, multiply, reenter the including preparation, and the evaluations are now expected to bloodstream, and infect red blood cells, which can lead to be completed by 2023. Its goal is to enable an updated WHO disease symptoms. policy recommendation—as soon as late 2021 or early 2022— on the possible broader use of RTS,S in African children by RTS,S has been rigorously tested through a series of clinical generating additional evidence on feasibility, impact, and trials.1,2 The final Phase 3 efficacy and safety trial—the largest safety—all in the context of routine use. malaria vaccine trial in Africa to date—involved 15,459 infants and young children and was conducted by 11 clinical research As part of the implementation program, GSK is conducting centers in seven African countries (Burkina Faso, Gabon, Phase 4 studies in parts of the pilot areas. These studies—as Ghana, Kenya, Malawi, Mozambique, and Tanzania).3 required and standard for a new vaccine—will gather additional information on the vaccine’s effectiveness and on any side The final results of the Phase 3 trial demonstrated that, among effects associated with routine use. Data collected through the children who received four doses, the vaccine prevented Phase 4 studies will complement data from the pilot evaluations approximately 4 in 10 (39%) cases of malaria and 3 in 10 (29%) led by WHO. PATH is working with WHO in several areas, cases of severe malaria over a four-year period.3 The fourth including on economic assessments and the qualitative dose prolonged protection against clinical malaria, with 1,774 assessment of behavior change that may occur during vaccine cases of malaria averted per 1,000 children vaccinated, on introduction. GSK is donating up to 10 million doses for use in average, across all sites (site-specific cases averted ranged the MVIP. Other evaluation partners include a wide range of from 205 to 6,565 per 1,000 children vaccinated). Vaccine academic, medical, and other research organizations. efficacy waned over time, and further studies have been undertaken to assess longer-term efficacy and the need for Additional funding is being sought to ensure completion of the additional doses. pilot introduction and associated evaluations, and to assure the longer-term supply of the vaccine. An article published in The Lancet Infectious Diseases in 2019 reported the results of a study on the longer-term impact of the References: vaccine, with a focus on severe malaria.4 The study followed 1. Alonso P, Aponte J, Aide P, et al. Efficacy of the children who participated at three of the 11 research centers for RTS,S/AS02A vaccine against Plasmodium falciparum an additional three years, totaling seven years. Results showed infection and disease in young African children: randomized that the incidence of severe malaria decreased as children got controlled trial. The Lancet. 2004;364 (9443):1411-1420. doi: older, regardless of whether children received the vaccine, and 10.1016/S0140-6736(04)17223-1. that there was no evidence of rebound of severe malaria 2. Alonso P, Aponte J, Aide P, et al. Safety of the RTS,S/AS02D following the recommended four doses of the vaccine. candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomized controlled Regulatory and policy review phase 1/2b trial. The Lancet. 2007;370 (9598): 1543-1551. doi: 10.1016/S0140-6736(07)61542-6. The EMA’s assessment of RTS,S is part of its cooperation with 3. RTS,S Clinical Trials Partnership. Efficacy and safety of WHO to address diseases of major public health importance RTS,S/AS01 malaria vaccine with or without a booster dose in around the world, which requires medicinal products to meet the infants and children in Africa: Final results of a phase 3, same standards as those intended for use in the European individually randomized, controlled trial. The Lancet. 2015;386 Union. The EMA found that the vaccine’s quality and risk-benefit (9988): 31-45. doi: 10.1016/S0140-6736(15)60721-8. profile are favorable from a regulatory perspective.5 4. Tinto H, et al. Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomized Following the EMA decision, and after a thorough review of the control trial. Lancet Infectious Diseases. clinical trial results and contextual elements such as feasibility of 2019;doi:10.1016/S1473-3099(19)30300-7; see also Dicko A, implementation, potential public health impact, and likely cost- Greenwood B. Malaria vaccination and rebound malaria. Lancet Infectious Diseases. 2019;doi:10.1016/S1473- effectiveness of the vaccine, WHO’s independent advisory 3099(19)30282-8. committees for immunization and malaria—the Strategic 5. First malaria vaccine receives positive scientific opinion from Advisory Group of Experts (SAGE) on Immunization and the EMA [press release]. European Medicines Agency; July 24, Malaria Policy Advisory Committee (MPAC)—jointly called for 2015. http://bit.ly/1elUa6Z. pilot implementation of the vaccine in settings of moderate-to- 6. World Health Organization. Weekly Epidemiological Record. high malaria parasite transmission in sub-Saharan Africa. 2016;91(4): 33-52. http://www.who.int/wer.